Background and Objectives: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. Methods: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. Results: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. Discussion:Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

1.
Holcomb
NC
,
Bautista
RM
,
Jarrett
SG
,
Carter
KM
,
Gober
MK
,
D'Orazio
JA
.
Camp-mediated regulation of melanocyte genomic instability: a melanoma-preventive strategy
.
Adv Protein Chem Struct Biol
.
2019
;
115
(
115
):
247
95
. .
2.
Swope
VB
,
Abdel-Malek
ZA
.
Mc1r: front and center in the bright side of dark eumelanin and DNA repair
.
Int J Mol Sci
.
2018
;
19
:
2667
.
3.
Swope
VB
,
Abdel-Malek
ZA
.
Significance of the melanocortin 1 and endothelin b receptors in melanocyte homeostasis and prevention of sun-induced genotoxicity
.
Front Genet
.
2016
;
7
:
146
. .
4.
Nasti
TH
,
Timares
L
.
Mc1r, eumelanin and pheomelanin: their role in determining the susceptibility to skin cancer
.
Photochem Photobiol
.
2015
;
91
(
1
):
188
200
. .
5.
Krude
H
,
Biebermann
H
,
Luck
W
,
Horn
R
,
Brabant
G
,
Gruters
A
.
Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by pomc mutations in humans
.
Nat Genet
.
1998
;
19
(
19
):
155
7
. .
6.
Low
MJ
.
Neuroendocrinology: new hormone treatment for obesity caused by pomc-deficiency
.
Nat Rev Endocrinol
.
2016
;
12
(
11
):
627
8
. .
7.
Muller
TD
,
Tschop
MH
,
O'Rahilly
S
.
Metabolic precision medicines: curing pomc deficiency
.
Cell Metab
.
2016
;
24
(
2
):
194
5
. .
8.
Kühnen
P
,
Krude
H
,
Biebermann
H
.
Melanocortin-4 receptor signalling: importance for weight regulation and obesity treatment
.
Trends Mol Med
.
2019
;
25
(
25
):
136
48
. .
9.
Clement
K
,
Biebermann
H
,
Farooqi
IS
,
Van der Ploeg
L
,
Wolters
B
,
Poitou
C
,
Mc4r agonism promotes durable weight loss in patients with leptin receptor deficiency
.
Nat Med
.
2018
;
24
(
24
):
551
5
. .
10.
Kühnen
P
,
Clément
K
,
Wiegand
S
,
Blankenstein
O
,
Gottesdiener
K
,
Martini
LL
,
Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist
.
N Engl J Med
.
2016
;
375
(
3
):
240
6
. .
11.
Clement
K
,
Biebermann
H
,
Farooqi
IS
,
Van der Ploeg
L
,
Wolters
B
,
Poitou
C
,
Mc4r agonism promotes durable weight loss in patients with leptin receptor deficiency
.
Nat Med
.
2018
.
12.
Kuhnen
P
,
Clement
K
,
Wiegand
S
,
Blankenstein
O
,
Gottesdiener
K
,
Martini
LL
,
Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist
.
N Engl J Med
.
2016
;
375
(
375
):
240
6
. .
13.
Ocampo-Garza
J
,
Salinas-Santander
M
,
Welsh
O
,
Herz-Ruelas
M
,
Ocampo-Candiani
J
.
Expression of melanocortin 1 receptor before and after narrowband uvb phototherapy treatment in patients with stable vitiligo: a prospective study
.
Exp Ther Med
.
2020
;
19
(
19
):
1649
54
. .
14.
Wright
CY
,
Karsten
AE
,
Wilkes
M
,
Singh
A
,
du Plessis
J
,
Albers
PN
,
Diffuse reflectance spectroscopy versus mexameter([r]) mx18 measurements of melanin and erythema in an african population
.
Photochem Photobiol
.
2016
;
92
:
632
6
.
15.
Clarys
P
,
Alewaeters
K
,
Lambrecht
R
,
Barel
AO
.
Skin color measurements: comparison between three instruments: the chromameter(r), the dermaspectrometer(r) and the mexameter(r)
.
Skin Res Technol
.
2000
;
6
(
6
):
230
8
. .
16.
Hayashi
M
,
Okamura
K
,
Araki
Y
,
Suzuki
M
,
Tanaka
T
,
Abe
Y
,
Spectrophotometer is useful for assessing vitiligo and chemical leukoderma severity by quantifying color difference with surrounding normally pigmented skin
.
Skin Res Technol
.
2018
;
24
(
24
):
175
9
. .
17.
Dwyer
T
,
Muller
HK
,
Blizzard
L
,
Ashbolt
R
,
Phillips
G
.
The use of spectrophotometry to estimate melanin density in caucasians
.
Cancer Epidemiol Biomarkers Prev
.
1998
;
7
(
3
):
203
6
.
18.
Treesirichod
A
,
Chansakulporn
S
,
Wattanapan
P
.
Correlation between skin color evaluation by skin color scale chart and narrowband reflectance spectrophotometer
.
Indian J Dermatol
.
2014
;
59
(
59
):
339
42
. .
19.
van der Mei
IA
,
Blizzard
L
,
Stankovich
J
,
Ponsonby
AL
,
Dwyer
T
.
Misclassification due to body hair and seasonal variation on melanin density estimates for skin type using spectrophotometry
.
J Photochem Photobiol B, Biol
.
2002
;
68
(
1
):
45
52
. .
20.
Fullerton
A
,
Fischer
T
,
Lahti
A
,
Wilhelm
KP
,
Takiwaki
H
,
Serup
J
.
Guidelines for measurement of skin colour and erythema. A report from the standardization group of the european society of contact dermatitis
.
Contact Dermatitis
.
1996
;
35
(
35
):
1
10
. .
21.
Pershing
LK
,
Tirumala
VP
,
Nelson
JL
,
Corlett
JL
,
Lin
AG
,
Meyer
LJ
,
Reflectance spectrophotometer: The dermatologists’ sphygmomanometer for skin phototyping?
J Invest Dermatol
.
2008
;
128
(
7
):
1633
40
. .
22.
Sharma
VK
,
Gupta
V
,
Jangid
BL
,
Pathak
M
.
Modification of the fitzpatrick system of skin phototype classification for the indian population, and its correlation with narrowband diffuse reflectance spectrophotometry
.
Clin Exp Dermatol
.
2018
;
43
(
43
):
274
80
. .
23.
Geert Verbeke
GM
.
Linear mixed models for longitudinal data
.
New York
:
Springer-Verlag
;
2000
.
24.
Verbeke
G
,
Molenberghs
G
.
Linear mixed models for longitudinal data
.
Springer
;
2000
.
25.
Valverde
P
,
Healy
E
,
Jackson
I
,
Rees
JL
,
Thody
AJ
.
Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans
.
Nat Genet
.
1995
;
11
(
3
):
328
30
. .
26.
Valverde
P
,
Healy
E
,
Sikkink
S
,
Haldane
F
,
Thody
AJ
,
Carothers
A
,
The asp84glu variant of the melanocortin 1 receptor (mc1r) is associated with melanoma
.
Hum Mol Genet
.
1996
;
5
(
5
):
1663
6
. .
27.
Kadekaro
AL
,
Leachman
S
,
Kavanagh
RJ
,
Swope
V
,
Cassidy
P
,
Supp
D
,
Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation
.
FASEB J
.
2010
;
24
(
10
):
3850
60
. .
28.
de Torre
C
,
Garcia-Casado
Z
,
Martinez-Escribano
JA
,
Botella-Estrada
R
,
Banuls
J
,
Oliver
V
,
Influence of loss of function mc1r variants in genetic susceptibility of familial melanoma in spain
.
Melanoma Res
.
2010
;
20
(
20
):
342
8
. .
29.
Matichard
E
,
Verpillat
P
,
Meziani
R
,
Gerard
B
,
Descamps
V
,
Legroux
E
,
Melanocortin 1 receptor (mc1r) gene variants may increase the risk of melanoma in france independently of clinical risk factors and uv exposure
.
J Med Genet
.
2004
;
41
(
2
):
e13
. .
30.
Kennedy
C
,
ter Huurne
J
,
Berkhout
M
,
Gruis
N
,
Bastiaens
M
,
Bergman
W
,
Melanocortin 1 receptor (mc1r) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color
.
J Invest Dermatol
.
2001
;
117
(
117
):
294
300
. .
31.
Tatro
JB
,
Entwistle
ML
,
Lester
BR
,
Reichlin
S
.
Melanotropin receptors of murine melanoma characterized in cultured cells and demonstrated in experimental tumors in situ
.
Cancer Res
.
1990
;
50
(
4
):
1237
42
.
32.
Collet
TH
,
Dubern
B
,
Mokrosinski
J
,
Connors
H
,
Keogh
JM
,
Mendes de Oliveira
E
,
Evaluation of a melanocortin-4 receptor (mc4r) agonist (setmelanotide) in mc4r deficiency
.
Mol Metab
.
2017
;
6
(
6
):
1321
9
. .
33.
Ha
T
,
Rees
JL
.
Red hair–a desirable mutation?
J Cosmet Dermatol
.
2002
;
1
(
2
):
62
5
. .
34.
Feller
L
,
Masilana
A
,
Khammissa
RA
,
Altini
M
,
Jadwat
Y
,
Lemmer
J
,
Melanin: the biophysiology of oral melanocytes and physiological oral pigmentation
.
Head Face Med
.
2014
;
10
(
10
):
8
. .
35.
Bergthorsdottir
R
,
Leonsson-Zachrisson
M
,
Oden
A
,
Johannsson
G
.
Premature mortality in patients with addison's disease: a population-based study
.
J Clin Endocrinol Metab
.
2006
;
91
(
12
):
4849
53
. .
36.
Bensing
S
,
Brandt
L
,
Tabaroj
F
,
Sjoberg
O
,
Nilsson
B
,
Ekbom
A
,
Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency
.
Clin Endocrinol
.
2008
;
69
(
69
):
697
704
. .
37.
Minder
EI
,
Barman-Aksoezen
J
,
Schneider-Yin
X
.
Pharmacokinetics and pharmacodynamics of afamelanotide and its clinical use in treating dermatologic disorders
.
Clin Pharmacokinet
.
2017
;
56
(
8
):
815
23
. .
38.
Dhillon
S
,
Keam
SJ
.
Bremelanotide: first approval
.
Drugs
.
2019
;
79
(
79
):
1599
606
. .
39.
Lim
HW
,
Grimes
PE
,
Agbai
O
,
Hamzavi
I
,
Henderson
M
,
Haddican
M
,
Afamelanotide and narrowband uv-b phototherapy for the treatment of vitiligo: a randomized multicenter trial
.
JAMA Dermatol
.
2015
;
151
(
1
):
42
50
. .
40.
El Tahlawi
S
,
Abdel Halim
DM
,
El Hadidi
H
,
Fawzy
MM
,
Hegazy
RA
,
Ezzat
M
,
Estimation of Homocysteine Level and Methylenetetrahydrofolate Reductase (MTHFR) Gene and Cystathionine B Synthase (CBS) Gene Polymorphisms in Vitiligo Patients
.
Skin Pharmacol Physiol
.
2020
;
33
(
1
):
38
43
. .
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